Design, synthesis and anticancer activity evaluation of novel C14 heterocycle substituted epi-triptolide

•Synthesis of novel C14-aryl heterocycle substituted epi-triptolide analogs.•In vitro antitumor activity evaluation.•Compounds with triazolylmethyl substituents proved to be inactive.•Compounds with aryl heterocycle aminomethyl substituents showed potent cytotoxity.•The structure–activity relationship of triptolide analogs were summarized.

Two series of novel C14 heterocycle substituted epi-triptolide derivatives as potential anticancer agents were synthesized and tested for their cytotoxicity against SKOV-3 and PC-3 tumor cell lines. The introduction of C14β-aryl heterocycle aminomethyl substituent to the leading compound was found to be an effective modification method to retain the potent anticancer activity. Meanwhile, the series of epi-triptolide derivatives (21–40) with C14α-hydroxyl group, still retained the natural product's cytotoxicity. This is apparently challenges the classical structure–activity relationship of triptolide that considers the C14β-hydroxyl group to be essential for its anticancer activity.

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